WO99/44991 and WO01/17961 disclose a process for preparing Compound (I) as depicted in Reaction Scheme 1:
wherein R represents C1-4 alkyl or C1-4 haloalkyl, and P and P2 each represent the same or different protecting group.
WO99/44991 specifically describes a process from Compound (II) to Compound (3) in the above Reaction Scheme 1, which consists of two reduction steps of the nitrile group and one protection step of the amine group.
Compound (1) is produced from Compound (II) by a hydrogenation process using such a catalyst as Ra—Ni, etc. for the first reduction of nitrile group. As the solvent, a mixture of water and isopropyl alcohol is used in an amount of 2 to 20 equiv with respect to Compound (II).
Compound (2) is produced from Compound (1) by protecting the amine group. As the protecting group, formyl, acetyl, trifluoroacetyl, benzoyl, p-toluenesulfonyl, methoxycarbonyl, ethoxycarbonyl, t-butoxycarbonyl, benzyloxycarbonyl, p-methoxy-benzyl, trityl, tetrahydropyranyl, pivaloyl, etc. may be used. Among these protecting groups, t-butoxycarbonyl is particularly preferred. However, (BOC)2O used for the introduction of the t-butoxycarbonyl group is an expensive reagent to contribute about ⅓ of the total cost for preparing Compound (2) from Compound (1). Furthermore, the reaction temperature is difficult to control due to high exothermic and fast reaction rate. Failure of the control of the reaction temperature led to the formation of the dimer of Compound (2). Also, Compound (2) should be separated through an extractive work-up and solidification process. These work-up processes make this process complicate.
Compound (3) is produced from Compound (2) by the second hydrogenation process using Pd/C catalyst. The catalyst is used in an amount of 0.5-20% by weight, and an amine or buffer solution is used to prevent reduction of the carbonyl group at 3-position of the pyrrolidine ring.
The process for preparing Compound (I) from Compound (4) is disclosed in WO001/17961, wherein the protecting group is removed using methanesulfonic acid to form a salt. However, this process requires two recrystallization processes to produce high quality product. These operations lowered the productivity and resulted in low yield.
Differently from the Reaction Scheme 1 above, EP 0 688 772 A1 describes a process for preparing Compound (4) from Compound (II) as depicted in Reaction Scheme 2.
wherein R represents C1-4 alkyl or C1-4 haloalkyl, and P and P′ each represent the same or different protecting group.
EP 0 688 772 A1 provides a process for preparing Compound (4) from Compound (II) wherein the carbonyl and nitrile groups are reduced simultaneously to give the amino alcohol intermediate, and the alcohol group is selectively oxidized to give the carbonyl group again. This process requires reagents difficult to be applied to the industrial production, and so has little merit compared with the process of WO99/44991. Particularly, this process uses a homogeneous catalyst for the hydrogenation of the nitrile group, but preparation of the homogeneous catalyst and its recovery and reproduction after the reaction are not easy.